PROJECT SUMMARY/ABSTRACT Age-related declines in skeletal muscle mass (sarcopenia) can result in a loss of mobility, independence and the ability to perform everyday activities, and the problem can be exacerbated by muscle fatigue. Although studies on isometric (static) contractions often report that old adults fatigue less than young adults, the opposite is generally observed in dynamic contractions, which are more relevant for performing daily activities. The mechanisms for the age-related increased fatigability and losses in muscle power during dynamic contractions are not known but are essential to identify to help improve physical function and quality of life in the elderly. The goal of this proposal is to identify the causes for the increased fatigability in old adults by integrating advanced techniques to study fatigue at the level of the single muscle fiber (muscle biopsies) and within the entire neuromuscular system (transcranial magnetic stimulation). The hypothesis is that old adults experience greater fatigue than young adults during dynamic contractions as a result of age-related differences within the muscle (peripheral fatigue) rather than in the nervous system (central fatigue). The study design will also test for differences in muscle fatigability between men and women and old (60-74 yrs) and very old (?75 yrs) adults. Studies on old women and very old adults are limited but particularly important because both cohorts suffer from accelerated age-related losses in muscle mass and function making them more susceptible to the detrimental effects of muscle fatigue. In Aim 1, I will test the hypothesis that age-related increases in peripheral fatigue during dynamic contractions will result in greater reductions in force and power of the knee extensors in old compared to young adults. I will use magnetic stimulation of the motor cortex and electrical stimulation of the femoral nerve to test whether the amount of supraspinal and peripheral fatigue differs with age or sex during dynamic fatiguing contractions. In Aim 2, I will use single fibers isolated from needle biopsies of the vastus lateralis to test the hypothesis that old adult muscle fibers have a reduced contractile efficiency and are more sensitive to the depressive effects of the fatiguing metabolites that accumulate in the muscle during dynamic contractions compared to young adult muscle fibers. These studies will generate a comprehensive understanding of the causes of fatigue in old men and women that will translate into the design and testing of novel exercise interventions that target the identified mechanisms of age-related fatigability to improve muscle power, physical function and quality of life in the elderly.